Tirapazamine is a bioreductive agent that preferentially kills hypoxic cells. Tirapazamine, i.e., 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR-4233) has the structural formula ##STR1## When given as multiple injections in conjunction with fractionated irradiation, tirapazamine kills hypoxic cells, increases tumor cell kill while sparing normal tissue in mouse SCCVII and other tumors as reported by: Brown, J. M., Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors, Cancer Res. 50:7745-7749 (1990) and Brown, J. M. et al, SR 4233: A tumor specific radiosensitizer active in fractionated radiation regimens, Radiother, and Oncol., 20:151-156 (1991). Brown has considered that tumor hypoxia may actually be of a therapeutic advantage when combining a hypoxic cytotoxin such as tirapazamine with fractionated irradiation: Brown, J. M. et al., Tumor hypoxia: the picture has changed in the 1990s, Int. J Radiat. Biol., 65:95-102(1994); and Brown, J. M. et al, Therapeutic advantage of hypoxic cells in tumors: a theoretical study, J Nat. Can. Inst., 83:178-185 (1991).
International Application No. PCT/US89/01037 discloses 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. Related patents include: U.S. Pat. No. 5,175,287 which discloses the use of 1,2,4-benzotriazine oxides in conjunction with radiation for treatment of tumors. The 1,2,4-benzotriazine oxides sensitize the tumor cells to radiation and make them more amenable to this treatment modality. U.S. Pat. Nos. 3,868,372 and 4,001,410 which disclose the preparation of 1,2,4-benzotriazine oxides; and U.S. Pat. Nos. 3,991,189 and 3,957,799 which disclose derivatives of 1,2,4-benzotriazine oxides.
Paclitaxel is a natural product with antitumor activity. The chemical name for paclitaxel is 5.beta.,20-Epoxy-1,2.alpha.,4,7.beta.,10.beta.,13.alpha.-hexahydroxytax-11 -en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following structural formula: ##STR2## Paclitaxel is a white to off-white crystalline powder with the empirical formula C.sub.47 H.sub.51 NO.sub.14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217.degree. C.
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Cisplatin is a platinum coordination complex that is used as a cancer chemotherapeutic agent. Cisplatin, i.e., cis-diamminedichloroplatinum, has a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position and the structural formula: ##STR3## It is a white powder (m.p. .about.207.degree. C.) with the molecular formula PtCl.sub.2 H6N.sub.2 and a molecular weight of 300.1. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. Due to its chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme catalyzed metabolism.
Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutane-dicarboxylato(2)-0,0']-, (SP-4-2). Carboplatin has the following structural formula: ##STR4## Carboplatin is a crystalline powder with the molecular formula C.sub.6 H.sub.12 N.sub.2 O.sub.4 Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone and dimethylacetamide. Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates.
Another platinum complex which has shown clinical promise is oxaliplatin. Oxaliplatin, i.e., cis-oxalato(trans-1-1,2-cyclohexanediamine) platinum (II) having the structure ##STR5## is described in U.S. Pat. No. 4,169,846. Related patents include: U.S. Pat. No. 5,290,961; U.S. Pat. No. 5,298,642; U.S. Pat. No. 5,338,874; U.S. Pat. No. 5,420,319 and PCT/IB/00614.
Holden et al (1992) "Enhancement of Alkylating Agent Activity by SR-4233 in the FSaIIC Murine Fibrosarcoma" JNCI 84: 187-193 discloses the use of SR-4233, also known as tirapazamine, in combination with an antitumor alkylating agent. The four antitumor alkylating agents, cisplatin, cyclophosphamide, carmustine and melphalan, were each tested to examine the ability of tirapazamine to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents. Tirapazamine was tested alone and in combination with varying amounts of each of the antitumor alkylating agents. When SR-4233 was administered just before single-dose treatment with cyclophosphamide, carmustine or melphalan marked dose enhancement leading to synergistic cytotoxic effects on tumor cells was observed. When SR-4233 was administered just prior to single-dose treatment with cisplatin, however, the dose enhancement lead to an additive effect, except at the highest dose level of cisplatin.
Brown, U.S. Pat. No. 5,484,612 discloses the treatment of cancer tumors with combinations of chemotherapy agents and 1,2,4-benzotriazine oxides.